Hexenyl radicals stereoselectivity

These methods are usually highly regio- and stereoselective and represent a breakthrough for synthetic chemistry using radicals. Giese quotes, as an example, that the cyclisation of the 5-hexenyl radical 8 affords the primary cyclopentylmethyl... 

On the other hand, Beckwith rules [22] are useful guidelines for predicting the stereoselectivity in the cyclisation of substituted hexenyl radicals i) 1- or 3-substituted radicals give preferentially cij-disubstituted cyclopentane derivatives and ii) 2- or 4-substituted radicals give mainly rrans-disubstituted derivatives. These rules can be explained in terms of 1,3-diaxial interactions present in a chair-like transition state. Some examples which demonstrate such an effect are [19b] ... 

By using either one of these photosystems, one-electron (3-activation of a,(3-unsaturated carbonyl compounds produced carbon-centered radical precursors which cyclize efficiently and stereoselectively to tethered activated olefins or carbonyl groups. The 1,2-anti-stereochemistry observed contrasts with the general trend of syn-stereochemistry expected in 5-hexenyl radical cyclizations. Application of this methodology was successfully demonstrated by the stereoselective synthesis of optically pure C-furanoside, starting from L-tartaric acid (Scheme 38) [57,58]. 

Key-step in the mechanistic scenario is a primary electron transfer process involving a sacrificial electron donor as exemplary shown for the triphenylphosphine case in Sch. 28. The 9,10-dicyanoanthracene radical anion (DCA -) thus generated undergoes a secondary thermal electron transfer to the unsaturated ketone. The resulting carbon-centered radical or radical anionic intermediate, subsequently cyclizes stereoselectively with a proximate olefin. The observed 1,2- 77 -stereochemistry of the C-C bond formation step contrasts with the commonly observed -stereoselectivity of 5-hexenyl radical cyclizations. As sacrificial electron donors, the... 

The propensity of 5-hexenyl radicals to undergo regio- and stereoselective cyclization to give cyclopentane derivatives was discussed in Chapter 2 (see Section 2.20). The radical adduct formed as a result of this step can either abstract a hydrogen atom from a suitable donor (usually tin hydride eq. 1, Scheme 3.39) or interact with another double or triple bond to form an additional C-C bond (eq. 2, Scheme 3.39). 

A diastereoselective cyclization of a 5-hexenyl radical linked to a carbohydrate scaffold was reported by Enholm et al. [171]. The authors used (+ )-isosorbit and ( —)-D-xylose as the chiral auxiliaries. The a,p-unsaturated bromo ester 262 derived from (-h )-isosorbit was reacted with tributyltinhydride and Lewis acids. The influence of the reaction temperature and of the solvent on the yield and stereoselectivity of the cyclization were also examined. Best results were obtained when ZnCl2 was used as Lewis acid at — 78°C (Scheme 10.85). The cyclization furnished the ester... 

Stereoselectivity in the cyclization of substituted 5-hexenyl radicals often follows the guidelines proposed by Beckwith1. According to this model, the early transition state of a 5-exo radical cyclization resembles a cyclohexane ring, preferring the chair over the boat conformation, with the substituents being pseudoequatorial rather than pseudoaxiai1 3 31. 

Simple model studies show that substitution at C-l or C-3 of the 5-hexenyl radical gives mainly c/.v-disubstituted cyclopentanes, whereas substitution at C-2 or C-4 leads mainly to tran.v-disub-stituted cyclopcntanes. A variety of theoretical treatments L 2 and experimental results now aid in the planning of highly stereoselective reactions, and allow predictions according to Beckwith s guidelines. 

The cyclizations of 5-hexenyl radicals sulfonylated at C-l show an unexpected stereoselectivity8. The sulfone cyclizations, for example, to an alkene or an enol ether, give cyclopcntane derivatives in good yields and with high trails selectivity. The stereoselectivity in this case is attributed to steric interactions and electronic repulsion between the oxygen at the sulfur and the enol ether oxygen. 

Replacement of C-3 in 5-hexenyl radicals by oxygen or nitrogen accelerates 5-exo cyclizations and, therefore, some of the most utilized radical cyclizations are employed for the formation of heterocycles. The stereoselectivity of the majority of such cyclizations follows the Beckwith... 

It must be also noted that 1,5-ring closures of 2-, 3-, or 4-alkyl-substituted 5-hexenyl radicals are also stereoselective 2- and 4-alkyl-substituted radicals afford mainly rrans-disubstituted (Cy5) products, while 3-substituted radicals (Section XI.4.A, Scheme 149) afford mainly the cis CyS products with ratios of up to 4 1. This observation has been generalized to the Cy5/Cy6 cyclization of peroxyl radicals. These results have been ascribed to a chair-like conformation of the transition state for the cyclizing (A ) radical with substituents preferentially occupying psewdo-equatorial positions. ... 

In the same way the vinylic analog of 411 at low tributylstannane concoi-tration affords a mixture of exo- and endo-2-methylnorbomane (71%) as the result of a double 1,5-cyclization in a Cy5/Cy6 case. The obtainment of good yields of bicyclic compounds from radicals such as 411 results from the stereoselective initial cyclization to the cis radical 412 as expected from the behavior of 3-substituted 5-hexenyl radicals, while the corresponding 2-substituted 3-hexenyl radicals, cyclizing as they do mainly to the tram radicals, give poor yields of bicyclic compounds. ... 

Radical cyclization of polyfunctional 5-hexenyl halides mediated by Et2Zn and catalyzed by nickel or palladium salts has been demonstrated to produce stereoselectively polyfunctional 5-membered carbo- and heterocycles [56, 57]. Based on this strategy a formal synthesis of methylenolactocin (11) was achieved (Scheme 20). The acetal 130, readily being built up by asymmetric alkylation of aldehyde 127 followed by reaction with butyl vinyl ether and NBS, served as the key intermediate for the construction of the lactone ring. Nickel(II)-catalyzed carbometallation was initiated with diethylzinc to yield exclusively the frans-disubstituted lactol 132, which could be oxidized directly by air to 134. Final oxidation under more forcing conditions then yielded the lactone (-)-75 as a known intermediate in the synthesis of (-)-methylenolactocin (11) [47aj. 

The mechanism of these transformations seems to be substrate-dependent and only the cycloisomerization of aryl and primary iodides was thought to proceed as shown in Scheme 31. The stereoselectivity of the isomerization of 110 to 111 is better accommodated with the intermediacy of l-methyl-5-hexenyl radical59. Later, it was proposed that the isomerization of 6 to 109 also proceeds via a radical-mediated atom transfer process initiated by homolytic fragmentation of an ate-complex intermediate 112 (Scheme 32)60. 

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